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Antibiotics are dead. Long live Postbiotics!

After investing a lot of money in research and far larger amounts in marketing, the food industry launched a herd of probiotic drinks and yoghurts onto the supermarket shelves. They promise a lot, in carefully non-legally binding language, but don’t deliver much because these bacteria don’t take (1). The day you stop eating them, they’re gone. They experience colonization resistance from the far larger numbers of bacteria which, unlike the lab-grown lactobacilli and bifidobacteria in your yoghurt, have inhabited your large bowel since birth and are perfectly adapted to living there. There is nowhere for the newbies to settle and no fuel for them to utilize, so they vacate the premises pdq. 

One of the very few products with real data behind it is Symprove, a foul-tasting (to me) water-based drink which contains four probiotic species. When drunk on an empty stomach Symprove passes quickly though, delivering significant numbers of the good bugs to the intestines where they are needed; but even Symprove requires constant use.

Symprove was initially tested in the artificial and malodorous M-SHIME gut model where it was shown to achieve colonization, increase butyrate levels, downgrade the production of pro-inflammatory chemokines and boost anti-inflammatory cytokine levels (2). It produced similar results in a very small sample of ulcerative colitis (UC) patients (3), and further in vitro work established inhibition of a number of pathogenic bacterial species (4). More and larger clinical trials followed, in which Symprove produced statistically significant improvements in symptom scores in patients with irritable bowel syndrome (IBS) (5), diverticular disease (6), and ulcerative colitis but not Chrohn’s Disease (7).

I have seen Symprove work in some difficult cases, but it is hard work drinking 70 mls of the stuff every morning. 

Next came the prebiotics. Unlike the probiotics, these food extracts have a long shelf-life. They do not require refrigeration, they have a neutral or slightly sweet taste and can be integrated into all kinds of foods, from biscuits to baloney and from beer to borscht. And because they provide fuel for the probiotic species that are already adapted to living in your unique inner environment, they really move the needle. If you use the right blend of prebiotic fibers and take enough of them, you can shift the entire colonic microbiome from gram negative dominance to gram positive dominance (8). This produces local health benefits ranging from increased regularity to the alleviation of IBS and IBD (8); systemic benefits which include significantly reduced risk of cancer and vascular disease; and a 30% reduction or more in the risk of early death (9). 

It makes excellent sense therefore to add 5 to 10 grams of blended prebiotic fibers to your daily diet.

When you do this you are merely replacing the fibers that the food industry has removed from their toxic, ultra-processed products. The one contra-indication to this kind of intervention is SIBO. SIBO sufferers know very well to avoid these compounds, as probiotic growth in the small bowel can be very uncomfortable. They should always use anti-adhesins to de-colonise the small bowel before taking a prebiotic.

Third up were the synbiotics. This confusing term, which harks back to such wonders of the natural world as the relationship between humans and dogs and a diminishingly small number of human relationships, was invented by the supplement industry to market combinations of probiotics and prebiotics. They don’t work; you can’t cram enough prebiotic fiber into a one or two a day capsule to make any difference to the microbiome. The combinatorial approach can be effective, however, when administered in food format.

Many years ago I gave the traditional Christmas lecture at the Royal Society of Medicine in London to an invited audience of scientifically orientated school leavers. The subject was functional foods, and at the start of the lecture I fed each of them a probiotic drink and a cereal bar containing 14 grams of prebiotic fiber. As the evening wore on the relative sobriety of the RSM shifted, imperceptibly, to the campfire scene in Blazing Saddles (10). It was an explosive evening, and one which encouraged many of those aspiring young scientists to become lawyers, financial advisers and plumbers.

More traditional examples of symbiotics are the fermented foods, which have long been associated with good health.

Kefir, kombucha, sauerkraut, tempeh, miso and kimchi all taste good to me. Natto is hard going but allegedly, if acclimatized to this as a child, you can tolerate it as an adult. Sourdough bread is another fermented food that is more widely consumed in the West. As it is baked the finished product contains no viable probiotic bacteria, but like all fermented foods, it contains postbiotics (see below). A few of these foods (kefir, natto and sauerkraut) have been investigated scientifically, but they are entirely unstandardized and the limited data available is not yet convincing.

Psychobiotics, a term originally coined by Ted Dynan and John Cryan at the University of Cork, refer to gut bacteria that exert positive effects on brain function. These include improved mood and behaviour, and possible protection against neurodegenerative disease. Dynan and Cryan are highly regarded scientists with an extensive list of publications in this area (ie 11-14) and I have cited their pioneering work in previous blog posts. Their papers provide a good introduction to the next gen approach, namely postbiotics, and these may be the most potent therapeutic tools of all.

The term postbiotic refers to metabolites produced by probiotic species which have suspected or proven health benefits. The term may be new to some, but references in the scientific literature go back as far as 1986 (15). The list ranges from simple fatty acids such as butyric, propionic and acetic acid and more complex molecules such as lipoteichoic acid, to immunogenic polysaccharides, a range of antimicrobial peptides (AMPS), and proteins such as surface layer protein and secreted protein which have positive effects on intestinal barrier function (16). Some of these, such as the proteins, act primarily locally. Many of them however are small molecules which are absorbed from the gut, enter the bloodstream and can impact tissues and organs elsewhere in the body. They form half of the dialogue where we and our microbiome meet, with our own intestinal secretions providing the other half.

 The pharmaceutical industry is feverishly developing semi-synthetic versions of some of these compounds, but I would avoid them. Tinkering with nature rarely improves on 600 million years of multicellular evolution, and generally comes with side effects. You can most easily and safely increase formation of these postbiotics yourself, by consuming more prebiotics. But, I hear you ask, what’s in it for me?

All of the thousands of microbiotal microbes indulge in biological warfare, each fighting their own corner against many other species, and on occasion forming alliances to fight off invading third parties. Think ‘Game of Thrones’; and then take it up a notch, keeping in mind that thrones can also be toilets. Some of these species are in broad alliance with us, others not so much, and their roles are not fixed. They may shift from friend to neutral to foe and back, depending on a range of internal (ie psychological, genetic, locational) and external (dietary) variables.

Symbionts such as the lactobacilli and bifidobacteria produce an astonishingly wide range of anti-bacterial (17, 18) and anti-fungal (19) compounds. Some of these are already used as food preservatives (20), others are being developed as new classes of anti-infectives (17, 18). Gram-positive symbionts live in the lumen and outer mucosal layers of the colon, which suits us just fine. Their postbiotic weapons keep gram-negative bacteria at bay, providing the symbionts with lebensraum. The benefit for us is that gram-negative bacteria which would otherwise consume the mucin, break down the mucosal layers, come into direct contact with the colonocytes and cause intense inflammation, are kept at a safe distance. The symbionts are our Mamluks, but they do not have free rein. Our colonic cells produce antimicrobial proteins of their own, which are up-regulated by the presence of symbionts and keep them in friendly check (21). Game of Thrones, anyone?

Other postbiotic compounds produced by our probiotic species do not kill gram negative bacteria per se, but protect us against them in other ways. Some of them, for example, help us by blocking the pro-inflammatory effects of the lipopolysaccharides in gram-negative cell walls (22, 23), and those of TNF-alpha (24). The advantage to the symbionts is more subtle in this case, and may be due to the fact that damping inflammation creates a better ecological niche for them (23). Others again stop dangerous pathogens such as P aeruginosa from forming biofilm (25-27), an important step in reducing virulence.

Symbiont postbiotics have a series of related effects on the gut wall itself, which are broadly anti-inflammatory and barrier-enhancing (16, 24), and may play a role in protecting us from IBD (23) and food allergy (28). IBD and food allergy have become more common since 1950 as prebiotic consumption has declined …and of course, the other problem which has increased vastly is colon cancer.

Various postbiotics have strong anti-cancer effects, including a series of cancer cell killing mechanisms which are clearly relevant in the gut (29, 30) and almost certainly in adjacent tissues such as the liver (24, 29, 32), the kidneys (32-34) and other abdominal organs (35). These postbiotics are highly selective, and unlike cancer drugs leave normal calls intact (29). The symbionts do not do this for our benefit, of course. From their perspective, preventing the host from developing and dying of cancer is simple self-interest. 

There are parallels in the world of parasites. Parasites with a long history in a particular host tend to be fairly benign, and may actually confer certain advantages on the host (36, 37) because evolution has ‘taught’ them that this enhances their own success. New parasites are usually far more destructive. Symbionts are probably symbionts because they invaded our eukaryote ancestors earlier in evolutionary history, while pathogens are late-comers who have not yet been civilized.

Postbiotics have effects on many other tissues too. The microbiome has long been linked to body weight and related metabolic issues (38-41), and the machinery behind this interesting connection is starting to emerge. The postbiotic compound acetate reduces mitochondrial efficiency in adipose tissue, shifting white fat to brown fat and thus helping with weight control (42-43). Other research teams have shown that the postbiotic compound muramyl dipeptide improves insulin sensitivity (44), a complementary and profoundly beneficial mode of action which, when combined with adipose browning and other postbiotic effects (40), would be enough to salvage many metabolic syndrome and T2D cases.

Postbiotics are also being investigated as possible elements in the connection between dysbiosis on the one hand, and autism (45, 47) and childhood infections (46, 47) on the other. Seppo Salminen at Turku University, an authority in these areas, believes these cases are not yet proven (47, 48), and that the term postbiotic still needs to be refined for regulatory and commercial use (48). Nevertheless, he is involved in investigating the possible use of postbiotics in infant formula (49). Others are looking at their incorporation in functional foods for adults (50), spurred on by the knowledge that specific postbiotics upregulate oxytocin (51), a pluripotent hormone that not only promotes love and better socialization but also improves wound healing.

Sadly, probiotics, prebiotics, synbiotics, psychobiotics and postbiotics will not make it into the food space any time soon because the food manufacturers, even if they were to integrate these compounds into their products, would not be allowed to talk about them. Regulatory agencies such as EFSA do not acknowledge that probiotics have any health benefits, and have made it illegal to claim that a food contains them. EFSA functionaries, errand boys sent by grocery clerks, grudgingly admit that the prebiotic fiber inulin ‘increases stool frequency’ but their costive nature blocks any further movement. They ignore the evidence and one really has to ask, once again, whose interests they represent. It is manifestly not the public.

Postscript

I write this post in Istanbul, a city I love and have enjoyed on many occasions. Due to the idiocy of politicians, I had to obtain a Covid test this morning in order to fly tomorrow to my next destination. The lab was clean and efficient, the test took 5 minutes and cost 250 Turkish lira, cash only. The clinic is not far from the austere Tesvikiye mosque, and as I strolled back through Taksim and Beyoglu I breathed in the precarious balance of order and chaos that is this great city’s signature. People here are busy, they are entrepreneurial, they are makers and builders, marketeers, grafters and grifters. The hum and buzz of local activity has not been crushed by the dead hand of crony command capitalism and oligopoly, as it has in the USA and Western Europe. Neo-liberal bureaucracy has not yet kneeled on the neck of the polloi; whatever you might think of Erdogan and his gang, they have not crushed the people. They remain engaged in a way that is no longer seen in North America, where the latest CDC survey found that between a quarter and a third of young people aged 18 to 24 had considered suicide in the last month alone (52). 

Turkey remains a bottom-up and therefore vigorous culture, and it shows in their use of words. I have always enjoyed the intrinsic ambiguity of language, but it is easy to forget when surrounded by the mother tongue. When travelling hopefully, it is a little more obvious. Coming toward me as I left the clinic was a pretty girl whose T-shirt displayed ‘Each day is a Piano’, with a line of text in smaller font I hoped might provide the explanation. It eventually revealed ‘Every Day,’ leaving me none the wiser. I pondered this for a block or two, wondering if the designer had been thinking in Italian. The idea of each day as a piano in an implausibly tall building, and climbing a flight of daily stairs to the eventual attic (or cellar) of afterlife, made enough sense to keep the wolves at bay for a while.

But then it was time to eat. On the menu was the Avci burger, a riddle wrapped in mystery inside an enigma. ‘As long as you would like to eat as much meat as you would expect,’ the menu suggested, ‘this burger is the hunter’s burger’. But how much meat do you expect? Would you really like to eat that much? And what kind of hunter? So many questions … I ducked them all and ordered gozleme, pickled artichoke heart and ful mudammes. The resulting postbiotic surge made me happy to be on the Bosporus and reminded me, in circuitous ways, of the Polish winged hussars whose charge at the gates of Vienna changed the course of world history.

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